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Methylmercury (MeHg) is a global environmental pollutant with neurotoxicity, which can easily crosses the blood–brain barrier and cause irreversible damage to the human central nervous system (CNS). CNS inflammation and autophagy are known to be involved in the pathology of neurodegenerative diseases. Meanwhile, MeHg has the potential to induce microglia-mediated neuroinflammation as well as autophagy. This study aims to further explore the exact molecular mechanism of MeHg neurotoxicity. We conducted in vitro studies using BV2 microglial cell from the central nervous system of mice. The role of inflammation and autophagy in the damage of BV2 cells induced by MeHg was determined by detecting cell viability, cell morphology and structure, reactive oxygen species (ROS), antioxidant function, inflammatory factors, autophagosomes, inflammation and autophagy-related proteins. We further investigated the relationship between the inflammatory response and autophagy induced by MeHg by inhibiting them separately. The results indicated that MeHg could invade cells, change cell structure, activate NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and autophagosome, release a large amount of inflammatory factors and trigger the inflammatory response and autophagy. It was also found that MeHg could disrupt the antioxidant function of cells. In addition, the inhibition of NLRP3 inflammasome alleviated both cellular inflammation and autophagy, while inhibition of autophagy increased cellular inflammation. Our current research suggests that MeHg might induce BV2 cytotoxicity through inflammatory response and autophagy, which may be mediated by the NLRP3 inflammasome activated by oxidative stress.

Reperfusion after ischemia would cause massive myocardial injury, which leads to oxidative stress (OS). Calcium homeostasis imbalance plays an essential role in myocardial OS injury. CaV1.2 calcium channel mediates calcium influx into cardiomyocytes, and its activity is modulated by a region of calpastatin (CAST) domain L, CSL54-64. In this study, the effect of Ahf-caltide, derived from CSL54-64, on myocardial OS injury was investigated. Ahf-caltide decreased the levels of LDH, MDA and ROS and increased heart rate, coronary flow, cell survival and SOD activity during OS. In addition, Ahf-caltide permeated into H9c2 cells and increased CaV1.2, CaVβ2 and CAST levels by inhibiting protein degradation. At different Ca2+ concentrations (25 nM, 10 μM, 1 mM), the binding of CSL to the IQ motif in the C terminus of the CaV1.2 channel was increased in a H2O2 concentration-dependent manner. CSL54-64 was predicted to be responsible for the binding of CSL to CaV1.2. In conclusion, Ahf-caltide exerted a cardioprotective effect on myocardial OS injury by stabilizing CaV1.2 protein expression. Our study, for the first time, proposed that restoring calcium homeostasis by targeting the CaV1.2 calcium channel and its regulating factor CAST could be a novel treatment for myocardial OS injury.

Abstract Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics, and currently used drugs cannot reverse the disease progress. Worse still, there are still challenges to be addressed to fully decipher the intricated pathogenesis. Thus, specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately needed. In this work, multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted agents. By utilizing an unbiased and time-resolved analysis of the transcriptome, proteome and phosphoproteome of a silicosis mouse model, we have verified the significant differences in transcript, protein, kinase activity and signaling pathway level during silicosis progression, in which the importance of essential biological processes such as macrophage activation, chemotaxis, immune cell recruitment and chronic inflammation were emphasized. Notably, the phosphorylation of EGFR (p-EGFR) and SYK (p-SYK) were identified as potential therapeutic targets in the progression of silicosis. To inhibit and validate these targets, we tested fostamatinib (targeting SYK) and Gefitinib (targeting EGFR), and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and fibrosis. Overall, our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.

Silicosis is one of the most important occupational diseases worldwide, caused by inhalation of silica particles or free crystalline silicon dioxide. As a disease with high mortality, it has no effective treatment and new therapeutic targets are urgently needed. Recent studies have identified FCER1A, encoding α-subunit of the immunoglobulin E (IgE) receptor FcεRI, as a candidate gene involved in the biological pathways leading to respiratory symptoms. FcεRI is known to be important in allergic asthma, but its role in silicosis remains unclear. In this study, serum IgE concentrations and FcεRI expression were assessed in pneumoconiosis patients and silica-exposed mice. The role of FcεRI was explored in a silica-induced mouse model using wild-type and FcεRI-deficient mice. The results showed that serum IgE concentrations were significantly elevated in both pneumoconiosis patients and mice exposed to silica compared with controls. The mRNA and protein expression of FcεRI were also significantly increased in the lung tissue of patients and silica-exposed mice. FcεRI deficiency significantly attenuated the changes in lung function caused by silica exposure. Silica-induced elevations of IL-1β, IL-6, and TNF-α were significantly attenuated in the lung tissue and bronchoalveolar lavage fluid (BALF) of FcεRI-deficient mice compared with wild-type controls. Additionally, FcεRI-deficient mice showed a significantly lower score of pulmonary fibrosis than wild-type mice following exposure to silica, with significantly lower hydroxyproline content and expression of fibrotic genes Col1a1 and Fn1. Immunofluorescent staining suggested FcεRI mainly on mast cells. Mast cell degranulation took place after silica exposure, as shown by increased serum histamine levels and β-hexosaminidase activity, which were significantly reduced in FcεRI-deficient mice compared with wild-type controls. Together, these data showed that FcεRI deficiency had a significant protective effect against silica-induced pulmonary inflammation and fibrosis. Our findings provide new insights into the pathophysiological mechanisms of silica-induced pulmonary fibrosis and a potential target for the treatment of silicosis.

To understand the mechanism underlying the regression of cardiac hypertrophy, we investigated the pathological changes after isoproterenol (ISO) withdrawal in ISO-induced cardiomyopathy models in rats and neonatal cardiomyocytes. Cardiac hypertrophy was induced in rats by two weeks of ISO administration; however, the hypertrophy did not regress after three weeks of natural maintenance after ISO administration was withdrawn (ISO-wdr group). The remaining hypertrophy in the ISO-wdr group was accompanied by a sustained increase in the level of phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII). Additionally, the increased expression levels of histone deacetylase 4 (HDAC4) and the CaV1.2 channel and amounts of CaMKII bound with HDAC4 and CaV1.2 were not recovered in the ISO-wdr group. The results in cardiomyocyte models were similar to those seen in rat models. Losartan, metoprolol or amlodipine neither ameliorated the increase in atrial natriuretic peptide nor inhibited the increase in p-CaMKII and bound CaMKII. In contrast, autocamtide-2-related inhibitor peptide, a CaMKII inhibitor, reduced these increases. This study investigated the phosphorylation status of CaMKII after hypertrophic stimulus was withdrawn for the first time and proposed that CaMKII as well as its complexes with CaV1.2 could be potential targets to achieve effective regression of cardiac hypertrophy.

N-methyl berbamine (N-MB) is a berberine derivative. Its analogue berbamine has been reported to have remarkable antiarrhythmic and ischemic protective effects. However, the pharmacological effects of N-MB are ill-defined. In this study, molecular docking was used to evaluate the binding of N-MB to CaV1.2 Ca2+ and KV11.1 K+ channels, and the effects of N-MB on action potential and ionic currents were observed in the ventricular myocytes of rabbits, HEK293 cells stably transfected with the hCaV1.2 gene and CHO cells stably transfected with hERG (human ether-a-go-go related gene). The results showed that N-MB was able to bind to both CaV1.2 and KV11.1 channels. Following a perfusion with N-MB, the durations of action potentials (APD20, APD50 and APD90) were extended, and the outward tail current, Itail, as well as the hERG current, IhERG, were inhibited, while the amplitude of action potential (APA) was only slightly reduced. N-MB also decreased the peak amplitude of the L-type Ca2+ channel current, ICaL, as well as the CaV1.2 current, ICaV1.2; this may limit the prolongation of APD. In conclusion, N-MB is a potent and natural antiarrhythmic multitarget drug that may elicit its antiarrhythmic effect through blocking both Ca2+ and K+ channel currents. Keywords: N-methyl berbamine, Action potential, Ca2+ current, K+ current, Multitarget

Abdominal aortic aneurysm (AAA) is potentially life-threatening in aging population due to the risk of aortic rupture and a lack of optimal treatment. The roles of different vascular and immune cells in AAA formation and pathogenesis remain to be future characterized. Single-cell RNA sequencing was performed on an angiotensin (Ang) II-induced mouse model of AAA. Macrophages, B cells, T cells, fibroblasts, smooth muscle cells and endothelial cells were identified through bioinformatic analyses. The discovery of multiple subtypes of macrophages, such as the re-polarization of Trem2+Acp5+ osteoclast-like and M2-like macrophages toward the M1 type macrophages, indicates the heterogenous nature of macrophages during AAA development. More interestingly, we defined CD45+COL1+ fibrocytes, which was further validated by flow cytometry and immunostaining in mouse and human AAA tissues. We then reconstituted these fibrocytes into mice with Ang II-induced AAA and found the recruitment of these fibrocytes in mouse AAA. More importantly, the fibrocyte treatment exhibited a protective effect against AAA development, perhaps through modulating extracellular matrix production and thus enhancing aortic stability. Our study reveals the heterogeneity of macrophages and the involvement of a novel cell type, fibrocyte, in AAA. Fibrocyte may represent a potential cell therapy target for AAA.

This study aimed to investigate the intracellular Mg2+ regulation of the L-type Ca2+ channels in guinea pig ventricular myocytes. By adopting the inside-out configuration of the patch clamp technique, single channel currents of the L-type Ca2+ channels were recorded at different intracellular Mg2+ concentrations ([Mg2+]i). At free [Mg2+]i of 0, 10−9, 10−7, 10−5, 10−3, and 10−1 M, 1.4 μM CaM + 3 mM ATP induced channel activities of 44%, 117%, 202%, 181%, 147%, and 20% of the control activity in cell-attached mode, respectively, showing a bell-shaped concentration-response relationship. Moreover, the intracellular Mg2+ modulated the Ca2+ channel gating properties, accounting for alterations in channel activities. These results imply that Mg2+ has a dual effect on the L-type Ca2+ channels: facilitation and inhibition. Lower [Mg2+]i maintains and enhances the basal activity of Ca2+ channels, whereas higher [Mg2+]i inhibits channel activity. Taken together, our data from the application of an [Mg2+]i series suggest that the dual effect of Mg2+ upon the L-type Ca2+ channels exhibits long open-time dependence.

Calmodulin (CaM) is well known as an activator of calcium/calmodulin-dependent protein kinase II (CaMKII). Voltage-gated sodium channels (VGSCs) are basic signaling molecules in excitable cells and are crucial molecular targets for nervous system agents. However, the way in which Ca2+/CaM/CaMKII cascade modulates NaV1.1 IQ (isoleucine and glutamine) domain of VGSCs remains obscure. In this study, the binding of CaM, its mutants at calcium binding sites (CaM12, CaM34, and CaM1234), and truncated proteins (N-lobe and C-lobe) to NaV1.1 IQ domain were detected by pull-down assay. Our data showed that the binding of Ca2+/CaM to the NaV1.1 IQ was concentration-dependent. ApoCaM (Ca2+-free form of calmodulin) bound to NaV1.1 IQ domain preferentially more than Ca2+/CaM. Additionally, the C-lobe of CaM was the predominant domain involved in apoCaM binding to NaV1.1 IQ domain. By contrast, the N-lobe of CaM was predominant in the binding of Ca2+/CaM to NaV1.1 IQ domain. Moreover, CaMKII-mediated phosphorylation increased the binding of Ca2+/CaM to NaV1.1 IQ domain due to one or several phosphorylation sites in T1909, S1918, and T1934 of NaV1.1 IQ domain. This study provides novel mechanisms for the modulation of NaV1.1 by the Ca2+/CaM/CaMKII axis. For the first time, we uncover the effect of Ca2+, lobe-specificity and CaMKII on CaM binding to NaV1.1.

Progressive fibrosing interstitial lung diseases (PF-ILDs) result in high mortality and lack effective therapies. The pathogenesis of PF-ILDs involves macrophages driving inflammation and irreversible fibrosis. Fc-g receptors (FcγRs) regulate macrophages and inflammation, but their roles in PF-ILDs remain unclear. We characterized the expression of FcγRs and found upregulated FcγRIIB in human and mouse lungs after exposure to silica. FcγRIIB deficiency aggravated lung dysfunction, inflammation, and fibrosis in silica-exposed mice. Using single-cell transcriptomics and in vitro experiments, FcγRIIB was found in alveolar macrophages, where it regulated the expression of fibrosis-related genes Spp1 and Ctss. In mice with macrophagespecific overexpression of FcγRIIB and in mice treated with adenovirus by intratracheal instillation to upregulate FcγRIIB, silica-induced functional and histological changes were ameliorated. Our data from three genetic models and a therapeutic model suggest that FcγRIIB plays a protective role that can be enhanced by adenoviral overexpression, representing a potential therapeutic strategy for PF-ILDs. [ABSTRACT FROM AUTHOR]

Background: Post-stroke spasticity (PSS) is the most common complication of stroke. Acupuncture is widely used in clinical practice for the treatment of PSS, and is therefore considered a common complementary treatment. Several systematic reviews (SRs) and meta-analyses (MAs) have demonstrated the efficacy and safety of acupuncture in the treatment of PSS; however, the quality of evidence of these studies has not been adequately assessed. Objective: To evaluate and summarize the SRs/MAs and inform future research and clinical practice on the efficacy and safety of acupuncture for PSS. Data sources and extracion: The following databases were searched from their dates of inception to March 26, 2023: PubMed, Embase, The Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, SinoMed, and Chinese Science and Technology Periodical Database (VIP), and grey literature were manually searched. Two reviewers independently completed literature retrieval, screening, and data extraction. Review appraisal: Systematic evaluation tools to Assess Systematic Reviews (AMSTAR) 2, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020 Checklist), and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system were used to systematically evaluate the methodological, reporting, and evidence quality of the SRs/MAs. Results: Overall, 226 papers were examined, and after careful consideration, 10 SRs/MAs were deemed eligible for inclusion. The AMSTAR 2 assessment revealed that one SR/MA had medium, one study had low, and the remaining eight studies had critically low methodological qualities. Additionally, four SRs/MAs completed more than 60 % of the PRISMA 2020 checklist. The GRADE system indicated that six outcomes were medium, 26 outcomes were low, and 24 outcomes were critically low. Conclusion: Based on the evidence, acupuncture may be a promising complementary treatment to improve post-stroke spasticity and quality of life. Further high-quality RCTs are needed in future studies to support the broader application of acupuncture for the treatment of PSS.

Abstract Transcutaneous auricular vagus nerve stimulation (taVNS) shows excellent effects on relieving clinical symptoms in migraine patients. Nevertheless, the neurological mechanisms of taVNS for migraineurs remain unclear. In recent years, voxel-wise degree centrality (DC) and functional connectivity (FC) methods were extensively utilized for exploring alterations in patterns of FC in the resting-state brain. In the present study, thirty-five migraine patients without aura and thirty-eight healthy controls (HCs) were recruited for magnetic resonance imaging scans. Firstly, this study used voxel-wise DC analysis to explore brain regions where abnormalities were present in migraine patients. Secondly, for elucidating neurological mechanisms underlying taVNS in migraine, seed-based resting-state functional connectivity analysis was employed to the taVNS treatment group. Finally, correlation analysis was performed to explore the relationship between alterations in neurological mechanisms and clinical symptoms. Our findings indicated that migraineurs have lower DC values in the inferior temporal gyrus (ITG) and paracentral lobule than in healthy controls (HCs). In addition, migraineurs have higher DC values in the cerebellar lobule VIII and the fusiform gyrus than HCs. Moreover, after taVNS treatment (post-taVNS), patients displayed increased FC between the ITG with the inferior parietal lobule (IPL), orbitofrontal gyrus, angular gyrus, and posterior cingulate gyrus than before taVNS treatment (pre-taVNS). Besides, the post-taVNS patients showed decreased FC between the cerebellar lobule VIII with the supplementary motor area and postcentral gyrus compared with the pre-taVNS patients. The changed FC of ITG-IPL was significantly related to changes in headache intensity. Our study suggested that migraine patients without aura have altered brain connectivity patterns in several hub regions involving multisensory integration, pain perception, and cognitive function. More importantly, taVNS modulated the default mode network and the vestibular cortical network related to the dysfunctions in migraineurs. This paper provides a new perspective on the potential neurological mechanisms and therapeutic targets of taVNS for treating migraine.

PurposeThe aim of this study is to compare the blood oxygen level–dependent (BOLD) fluctuation power in 96 frequency points ranging from 0 to 0.25 Hz between benign and malignant musculoskeletal (MSK) tumors via power spectrum analyses using functional magnetic resonance imaging (fMRI).Materials and methodsBOLD-fMRI and T1-weighted imaging (T1WI) of 92 patients with benign or malignant MSK tumors were acquired by 1.5-T magnetic resonance scanner. For each patient, the tumor-related BOLD time series were extracted, and then, the power spectrum of BOLD time series was calculated and was then divided into 96 frequency points. A two-sample t-test was used to assess whether there was a significant difference in the powers (the “power” is the square of the BOLD fluctuation amplitude with arbitrary unit) of each frequency point between benign and malignant MSK tumors. The receiver operator characteristic (ROC) analysis was used to assess the diagnostic capability of distinguishing between benign and malignant MSK tumors.ResultsThe result of the two-sample t-test showed that there was significant difference in the power between benign and malignant MSK tumor at frequency points of 58 (0.1508 Hz, P = 0.036), 59 (0.1534 Hz, P = 0.032), and 95 (0.247 Hz, P = 0.014), respectively. The ROC analysis of mean power of three frequency points showed that the area of under curve is 0.706 (P = 0.009), and the cutoff value is 0.73130. If the power of the tumor greater than or equal to 0.73130 is considered the possibility of benign tumor, then the diagnostic sensitivity and specificity values are 83% and 59%, respectively. The post hoc analysis showed that the merged power of 0.1508 and 0.1534 Hz in benign MSK tumors was significantly higher than that in malignant ones (P = 0.014). The ROC analysis showed that, if the benign MSK tumor was diagnosed with the power greater than or equal to the cutoff value of 1.41241, then the sensitivity and specificity were 67% and 68%, respectively.ConclusionThe mean power of three frequency points at 0.1508, 0.1534, and 0.247 Hz may potentially be a biomarker to differentiate benign from malignant MSK tumors. By combining the power of 0.1508 and 0.1534 Hz, we could better detect the difference between benign and malignant MSK tumors with higher specificity.

BackgroundChildhood maltreatment is known as a significant risk factor for later depression. However, there remains a lack of understanding about the mechanisms through which childhood maltreatment confers risk for depression. This study explores how Qi-stagnation constitution (QSC) and emotion regulation affect the link between childhood maltreatment and depressive symptoms in Chinese college students.MethodsWe recruited 2,108 college students aged 18–25 years between November 2020 and December 2021. Participants were required to complete four self-report questionnaires, including the Childhood Trauma Questionnaire-Short Form (CTQ-SF), Qi-Stagnation Constitution (QSC) subscale of the simplified Chinese Medicine Constitution Questionnaire, Difficulties in Emotion Regulation Scale (DERS), and the Beck Depression Inventory-II (BDI-II). Moderated mediation analyses were conducted.ResultsThere was a positive correlation between childhood maltreatment and QSC, while the QSC partially mediated the effect of childhood maltreatment on depressive scores in college students. In addition, emotion dysregulation moderated the association between QSC and depressive scores.ConclusionThese results enhance understanding of key factors influencing the link between childhood maltreatment and depressive symptoms among college students by combining the theory of TCM constitution with psychological processes. The development of strategies to prevent biased Qi-stagnation constitution and emotion dysregulation may help to improve college students’ mental health and strengthen the resilience of individuals to depression.

Background: The detection of intrinsic brain activity (iBA) could assist clinical assessment for disorder of consciousness (DOC) patients. Previous studies have revealed the altered iBA in thalamocortical, frontoparietal, and default mode network in DOC patients using functional connectivity (FC) analysis. However, due to the assumption of synchronized iBA in FC, these studied may be inadequate for understanding the effect of severe brain injury on the temporal organization of iBA and the relationship between temporal organization and clinical feature in DOC patients. Recently, the time delay estimation (TDE) and probabilistic flow estimation (PFE) were proposed to analyze temporal organization, which could provide propagation structure and propagation probability at whole-brain level. Methods: We applied voxel-wise TDE and PFE to assess propagation structure and propagation probability for the DOC patients and then applied the connectome-based predictive modeling (CPM) to predict clinical scores for patients based on the ROI-wise TDE and PFE. Results: We found that: 1) the DOC patients showed abnormal voxel-wise time delay (TD) and probabilistic flow (PF) in the precentral gyrus, precuneus, middle cingulate cortex, and postcentral gyrus, 2) the range of TD value in the patients was shorter than that in the controls, and 3) the ROI-wise TD had a better predictive performance for clinical scores of the patients compared with that based on ROI-wise PF. Conclusion: Our findings may suggest that the propagation structure of iBA could be used to predict clinical scores in DOC patients.

The aim of the present study was to isolate and characterize a complementary DNA (cDNA) clone encoding the calmodulin (CaM; GenBank accession no. FJ012165) gene from guinea pig hearts. The CaM gene was amplified from cDNA collected from guinea pig hearts and inserted into a pGEM®-T Easy vector. Subsequently, CaM nucleotide and protein sequence similarity analysis was conducted between guinea pigs and other species. In addition, reverse transcription-polymerase chain reaction (RT-PCR) was performed to investigate the CaM 3 expression patterns in different guinea pig tissues. Sequence analysis revealed that the CaM gene isolated from the guinea pig heart had ~90% sequence identity with the CaM 3 genes in humans, mice and rats. Furthermore, the deduced peptide sequences of CaM 3 in the guinea pig showed 100% homology to the CaM proteins from other species. In addition, the RT-PCR results indicated that CaM 3 was widely and differentially expressed in guinea pigs. In conclusion, the current study provided valuable information with regard to the cloning and expression of CaM 3 in guinea pig hearts. These findings may be helpful for understanding the function of CaM3 and the possible role of CaM3 in cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Decrement in processing speed (PS) is a primary cognitive morbidity in clinical populations and could significantly influence other cognitive functions, such as attention and memory. Verifying the usefulness of connectome-based models for predicting neurocognitive abilities has significant translational implications on clinical and aging research. In this study, we verified that resting-state functional connectivity could be used to predict PS in 99 older adults by using connectome-based predictive modeling (CPM). We identified two distinct connectome patterns across the whole brain: the fast-PS and slow-PS networks. Relative to the slow-PS network, the fast-PS network showed more within-network connectivity in the motor and visual networks and less between-network connectivity in the motor-visual, motor-subcortical/cerebellum and motor-frontoparietal networks. We further verified that the connectivity patterns for prediction of PS were also useful for predicting attention and memory in the same sample. To test the generalizability and specificity of the connectome-based predictive models, we applied these two connectome models to an independent sample of three age groups (101 younger adults, 103 middle-aged adults and 91 older adults) and confirmed these models could specifically be generalized to predict PS of the older adults, but not the younger and middle-aged adults. Taking all the findings together, the identified connectome-based predictive models are strong for predicting PS in older adults. The application of CPM to predict neurocognitive abilities can complement conventional neurocognitive assessments, bring significant clinical benefits to patient management and aid the clinical diagnoses, prognoses and management of people undergoing the aging process.

The eyes are our windows to the brain. There are differences in brain activity between people who have their eyes closed (EC) and eyes open (EO). Previous studies focused on differences in brain functional properties between these eyes conditions based on an assumption that brain activity is a static phenomenon. However, the dynamic nature of the brain activity in different eyes conditions is still unclear. In this study, we collected resting-state fMRI data from 21 healthy subjects in the EC and EO conditions. Using a sliding time window approach and a k-means clustering algorithm, we calculated the temporal properties of dynamic functional connectivity (dFC) states in the eyes conditions. We also used graph theory to estimate the dynamic topological properties of functional networks in the two conditions. We detected two dFC states, a hyper-connected State 1 and a hypo-connected State 2. We showed the following results: (i) subjects in the EC condition stayed longer in the hyper-connected State 1 than those in the EO; (ii) subjects in the EO condition stayed longer in the hypo-connected State 2 than those in the EC; and (iii) the dFC state transformed into the other state more frequently during EC than during EO. We also found the variance of the characteristic path length was higher during EC than during EO in the hyper-connected State 1. These results indicate that brain activity may be more active and unstable during EC than during EO. Our findings may provide insights into the dynamic nature of the resting-state brain and could be a useful reference for future rs-fMRI studies.

Nonylphenol (NP), a widely distributed, toxic, endocrine-disrupting chemical, has estrogenic properties. However, its cardiac effects remain unclear. In this study, the effects of NP on isolated guinea pig hearts were studied in three separate experiments. First, hearts were perfused with 10-7 M NP or 10-5 M NP to determine whether NP was toxic to isolated healthy hearts. Next, hearts were subjected to 50 min of ischemia and 60 min of reperfusion (I50R60) with 10-7 NP or 10-5 M NP to determine whether NP could aggravate ischemia/reperfusion (I/R) injury. Finally, the interaction of the cardio-protective agent 17β-estradiol (E2) with NP was studied using 107 M E2 10-7 M E2 plus 10-7 M NP, and 10-7 M E2 plus 10-5 M NP. Heart rate (HR) and coronary flow (CF) were significantly decreased and the leakage of lactate dehydrogenase (LDH) in effluent was increased in the 10-5 M NP group. However, there were no obvious changes in HR, CF, the leakage of LDH or creatine kinase (CK), or the activity of superoxide dismutase in either of the NP treatments in the I50R60 model. Treatment with 10-7 M E2 attenuated I/R injury by increasing HR, decreasing the leakage of LDH and CK, and decreasing infarct size. However, these effects were reversed by both concentrations of NP. These data demonstrate that NP had direct toxic effects on normal hearts and NP might disrupt the cardio-protective effects of E2 on I/R injury. [ABSTRACT FROM AUTHOR]

Bipolar disorder (BD) is characterized by emotion dysregulation and involves changes in the gray matter (GM) and white matter (WM). Although previous diffusion tensor imaging (DTI) studies reported changes in the diffusion properties of the deep WM (DWM) in BD patients, the diffusion properties of the superficial WM (SWM) are rarely investigated. In this study, we tried to determine whether the diffusion parameters of the SWM were altered in BD patients compared to controls and whether the changes were associated with the disrupted emotion regulation of the BD patients. We collected DTI data from 37 BD patients and 42 gender- and age-matched healthy controls (HC). Using probabilistic tractography, we defined a population-based SWM mask based on all the subjects. After performing the tract-based spatial statistical (TBSS) analyses, we identified the SWM areas in which the BD patients differed from the controls. This study showed significantly reduced fractional anisotropy in the SWM (FASWM) in the BD patients compared to the HC in the bilateral dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), medial prefrontal cortex (mPFC), and the left parietal cortex. Moreover, compared to the controls, the BD patients showed significantly increased mean diffusivity (MDSWM) and radial diffusivity (RDSWM) in the SWM in the right frontal cortex. This study presents altered cortico-cortical connections proximal to the regions related to the emotion dysregulation of BD patients, which indicated that the SWM may serve as the brain's structural basis underlying the disrupted emotion regulation of BD patients. The disrupted FASWM in the parietal cortex may indicate that the emotion dysregulation in BD patients is related to the cognitive control network. Keywords: Deep white matter (DWM), Diffusion tensor imaging, Cortico-cortical connection, Tract-based spatial statistics (TBSS), Probabilistic tractography

Background: pIREShyg2 has been widely used as a bicistronic expression vector. However, it is not known if the vector would affect the expression of cloned genes via nonsense-mediated mRNA decay (NMD), an mRNA surveillance system that degrades mRNA with a premature termination codon (PTC). In mammalian cells, the induction of NMD requires either a long 3'UTR or the presence of an exon-junction complex downstream of a PTC. The efficiency of NMD is greater when a PTC generates longer 3'UTR. pIREShyg2 provides the first cistron gene with a long 3'UTR consisting of a downstream intervening sequence (IVS), an internal ribosomal entry site (IRES) and the second cistron. Therefore, we hypothesized that the first cistron genes in pIREShyg2 are sensitized to NMD, which affects their expression levels. To examine this hypothesis, cDNAs encoding human granulocyte-macrophage colony-stimulating factor receptor β chain (βc) and its splice variant (βc79), in which the retention of a 79-base intron caused a frameshift generating 18 PTCs, were cloned into pIREShyg2 and stably expressed in a murine cell line, Ba/F3. Results: Compared with wild-type βc, the mRNA levels of βc79 were less than one tenth and decayed faster. Both translation inhibition and Upf1 knockdown led to significantly greater up-regulation of βc79 than wild-type βc. However, the use of a monocistronic pMT21 vector abolished the up-regulatory effects of translation inhibition and Upf1 knockdown on both wild-type βc and βc79, suggesting that the NMD is attributable to a structural determinant in pIREShyg2. The elimination of the intron and the proximal 3' 17 PTCs did not alter the greater effects of translation inhibition on βc79, suggesting that the first PTC, which determines 3'UTR length, was sufficient to enhance NMD efficiency. Thus, transcripts of PTC-harboring genes with longer 3'UTR are more efficiently degraded by the vectordependent NMD than those of wild-type genes with relatively shorter 3'UTR, resulting in minimized expression of truncated mutants. Conclusions: We conclude that pIREShyg2, which sensitizes its bicistronic transcripts to NMD, may be useful for studying NMD but should be avoided when maximum expressions of PTC-harboring genes are required. [ABSTRACT FROM AUTHOR]

The amplitude of low-frequency fluctuation (ALFF) measures low-frequency oscillations of the blood-oxygen-level-dependent signal, characterizing local spontaneous activity during the resting state. ALFF is a commonly used measure for resting-state functional magnetic resonance imaging (rs-fMRI) in numerous basic and clinical neuroscience studies. Using a test-retest rs-fMRI dataset consisting of 21 healthy subjects and three repetitive scans, we found that several key brain regions with high ALFF intensities (or magnitude) had poor reliability. Such regions included the posterior cingulate cortex, the medial prefrontal cortex in the default mode network, parts of the right and left thalami, and the primary visual and motor cortices. The above finding was robust with regard to different sample sizes (number of subjects), different scanning parameters (repetition time) and variations of test-retest intervals (i.e., intra-scan, intra-session, and inter-session reliability), as well as with different scanners. Moreover, the qualitative, map-wise results were validated further with a region-of-interest-based quantitative analysis using "canonical" coordinates as reported previously. Therefore, we suggest that the reliability assessments be incorporated in future ALFF studies, especially for the brain regions with a large ALFF magnitude as listed in our paper. Splitting single data into several segments and assessing within-scan "test-retest" reliability is an acceptable alternative if no "real" test-retest datasets are available. Such evaluations might become more necessary if the data are collected with clinical scanners whose performance is not as good as those that are used for scientific research purposes and are better maintained because the lower signal-to-noise ratio may further dampen ALFF reliability.

In order to adapt to the rapid development of green plant extract corrosion inhibitors, spinach extract (SPE) was selected as a corrosion inhibitor for Q235 steel in citric acid (CA) environment. SPE was extracted using a simple ethanol reflux method, and its main components, as well as their stability in CA, were confirmed through Fourier transform infrared spectroscopy (FTIR) and ultraviolet-visible spectroscopy (UV-Vis). The corrosion inhibition performance of SPE on Q235 steel in 0.5 mol/L CA solution was investigated using various methods including weight loss, dynamic potential polarization (PDP), linear polarization resistance (LPR), electrochemical impedance spectroscopy (EIS), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and contact angle measurements. Effects of temperature on the activation parameters (Ea, were studied by calculation. Results showed that chlorophyll was the main component of SPE, which exhibited good stability in a 0.5 mol/L CA solution. Furthermore, SPE significantly reduced the corrosion rate of Q235 steel in the 0.5 mol/L CA medium, acting as a mixed corrosion inhibitor for both cathodic and anodic reactions. With the increase of SPE concentration, both cathodic and anodic currents were reduced, active corrosion sites were blocked, the corrosion rate was decreased, and the corrosion inhibition efficiency was enhanced. The corrosion inhibition efficiency of Q235 steel obtained by weight loss method, PDP, LPR and EIS was more than 80% with 2.134 g/L of SPE concentration at 303 K. With the increase of system temperature, the corrosion inhibition efficiency of SPE on Q235 steel decreased, but the change was smaller. Compared to the blank system, the activation energy (Ea) of the system significantly increased after the addition of SPE. The effective components of SPE adsorped to the surface of Q235 steel in accordance with the Langmuir isotherm, predominantly through physical adsorption, and were characterized as monolayer adsorption. SPE exhibited good corrosion inhibition performance for Q235 steel in a 0.5 mol/L CA solution system, which was a green corrosion inhibitor with good application prospects in the pickling field. It could provide certain guidance for the development of plant extract-based corrosion inhibitors.